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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of diabetes mellitus on the pharmacokinetics of tacrolimus is not well characterized. We have compared tacrolimus 12-hour steady-state concentration-time profiles in diabetic (n = 11) and demographically matched nondiabetic (n = 9) stable kidney transplant recipients and derived a limited sampling strategy for the estimation of tacrolimus area under the concentration-time curve (AUC(0-12)). Tacrolimus concentration was measured by liquid chromatography tandem mass spectrometry and acetaminophen absorption method was used to characterize gastric emptying time. Demographic and biochemical characteristics were comparable between the two groups with the exception of significantly higher glycated hemoglobin levels in patients with diabetes (P = 0.02). Time to maximum concentration (T(max)) of acetaminophen was significantly longer in diabetics [D: 74.1 minute versus nondiabetics (ND): 29.3 minutes, P = 0.02]; however, tacrolimus T(max) was not significantly different (D: 121 minutes versus ND: 87 minutes, P = 0.15). Median (interquartile range) of tacrolimus AUC(0-12) was 114 (101-161) microg*hr/L in patients with diabetes and 113 (87-189) microg*hr/L in nondiabetics (P = 0.62). The following limited sampling equation [AUC(pred) (microg*hr/L) = 18.70 - 1.72 C(1 hr) - 4.09 C(2 hr) + 14.40 C(3 hr)] was derived from a training data set that included 10 patients. The correlation coefficient between model-predicted and observed AUC0-12 values was 0.999. Mean prediction error and root mean square error of the model-predicted values derived from the patients in validation data set were 0.04 and 17.48 microg*hr/L, respectively. In conclusion, it appears that diabetes has a modest effect on the rate but not the extent of tacrolimus absorption, and a three-point abbreviated sampling strategy common to both groups may prove useful for the estimation of tacrolimus exposure in kidney transplant recipients.
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PMID:Tacrolimus in diabetic kidney transplant recipients: pharmacokinetics and application of a limited sampling strategy. 1766 91

An animal model of post-transplant diabetes was induced in rats by treating them daily with 0.1 mg/kg body weight of tacrolimus (FK506) in two i.p. injections. Rats developed hyperglycaemia and glucose intolerance after 9 days of treatment. Pancreatic islets, isolated from treated rats on different days, showed a decreased capacity to secrete insulin in response to 20 mM glucose at days 7 and 14. This suppression of insulin secretion was preceded by a reduction of the islet insulin content on day 5 that was progressively decreasing until the end of the treatment (day 14). Islet content of insulin mRNAs, transcribed from rat insulin genes 1 and 2, was strongly suppressed, similar to the insulin content, at days 7 and 14. Islet mass was not strikingly modified by tacrolimus treatment: the DNA content was slightly decreased at the end (day 14) and the rate of islet cell apoptosis slightly increased. Tacrolimus-induced diabetes in the rat seems to be mainly provoked by a decreased insulin gene transcription with little or no alteration of islet mass. This explains that the observed suppression of all the islet and animal parameters studied was completely reversed 2 weeks after interrupting tacrolimus treatment.
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PMID:Tacrolimus-induced diabetes in rats courses with suppressed insulin gene expression in pancreatic islets. 1772 83

The mechanisms that regulate pancreatic beta cell mass are poorly understood. While autoimmune and pharmacological destruction of insulin-producing beta cells is often irreversible, adult beta cell mass does fluctuate in response to physiological cues including pregnancy and insulin resistance. This plasticity points to the possibility of harnessing the regenerative capacity of the beta cell to treat diabetes. We developed a transgenic mouse model to study the dynamics of beta cell regeneration from a diabetic state. Following doxycycline administration, transgenic mice expressed diphtheria toxin in beta cells, resulting in apoptosis of 70%-80% of beta cells, destruction of islet architecture, and diabetes. Withdrawal of doxycycline resulted in a spontaneous normalization of blood glucose levels and islet architecture and a significant regeneration of beta cell mass with no apparent toxicity of transient hyperglycemia. Lineage tracing analysis indicated that enhanced proliferation of surviving beta cells played the major role in regeneration. Surprisingly, treatment with Sirolimus and Tacrolimus, immunosuppressants used in the Edmonton protocol for human islet transplantation, inhibited beta cell regeneration and prevented the normalization of glucose homeostasis. These results suggest that regenerative therapy for type 1 diabetes may be achieved if autoimmunity is halted using regeneration-compatible drugs.
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PMID:Recovery from diabetes in mice by beta cell regeneration. 1778 32

Tacrolimus has been used extensively for immunosuppressive therapy in pediatric liver transplant recipients. However, patients who are exposed to high levels of serum tacrolimus tend to be associated with a higher incidence of significant nephrotoxicity, neurotoxicity, pruritus, alopecia, diabetes and infection. We herein report a child who developed increased serum transaminase levels and liver steatosis as a result of raised trough blood level of tacrolimus (30 ng/ml for 3 days) in association with rotavirus gastroenteritis.
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PMID:Fatty liver due to high levels of serum tacrolimus after liver transplantation. 1790 28

Tacrolimus (TRL) increases the incidence of new-onset diabetes mellitus after transplantation (NODAT). Little is known about whether conversion from TRL to cyclosporine A (CsA) improves glucose metabolism in patients with NODAT. We retrospectively analysed glucose metabolism parameters in 54 TRL-treated renal transplant patients who developed NODAT. Thirty-four were converted to CsA whereas 20 patients continued TRL. After conversion, fasting plasma glucose decreased from 146 +/- 64 to 104 +/- 20 mg/dl (P < 0.0001) and HbA1c levels decreased from 6.8 +/- 0.8% to 6.0 +/- 0.6% (P < 0.0001) after 1 year of follow-up. The remission rate of NODAT reached 42% (95% confidence interval 24-59%) 1 year after conversion versus 0% in the control group (P = 0.001). Blood pressure and lipid levels were stable after conversion although the use of statins significantly increased (P < 0.01). The conversion was safe in terms of graft function and acute rejection episodes. The 1-year patient survival and graft survival rate were 100%. In conclusion, our results suggest a significant improvement of glucose metabolism after conversion to CsA in renal transplant patients with NODAT.
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PMID:Conversion from tacrolimus to cyclosporine A for new-onset diabetes after transplantation: a single-centre experience in renal transplanted patients and review of the literature. 1797 Oct 33

Tacrolimus gained FDA approval for use in liver transplantation in 1994 and, approximately 3 years later, was approved for the prevention of acute rejection in kidney transplantation. Over the last decade tacrolimus has become the calcineurin inhibitor of choice for the prevention of rejection in renal transplantation. The objective of this study was to provide a review and update of the literature on the use of tacrolimus in renal transplantation. Numerous clinical trials have shown tacrolimus to be superior to cyclosporine in the prevention of acute rejection and recent trials have demonstrated superiority of tacrolimus over cyclosporine in terms of allograft survival. Post-transplant diabetes remains more common with tacrolimus than cyclosporine, despite lower doses of both tacrolimus and corticosteroids. A novel once-daily dosage form of tacrolimus has recently been developed and is approved for use in Europe. Tacrolimus remains an important immunosuppressant for the prevention of acute rejection. The prolonged-release formulation may improve compliance and possibly long-term outcomes.
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PMID:The role of tacrolimus in renal transplantation. 1831 64

Corticosteroids are a cornerstone of immunosuppressive therapy in renal transplantation despite their side effects and morbidity. Newer immunosuppressive agents may be more effective to allow corticosteroid sparing. An interim analysis of 60 completed out of 100 planned primary kidney transplant recipients is presented. All patients on tacrolimus (Prograf) and MMF (Cellcept) were randomized into two groups following a 1:1 distribution for early steroid reduction at posttransplant day 7 (G1; n = 31) versus to long-term maintenance steroids (G2; n = 29). Primary efficacy endpoints were composite endpoint of death, graft loss, or severe acute rejection at 6 and 12 months follow-up. Safety evaluation included severity and frequency of diabetes mellitus, hypertension, hyperlipidemia, leukopenia, infection, malignancy, and severe adverse events. Mean age was 39.1 years, with 45.0% males and 66.7% Caucasians. African-Americans were 25.8% in G1 and 27.6% in G2. One death occurred in each group, as well as one case of severe (Banff III) rejection in G1 (P = 1.00). The incidence of rejection episodes between groups was not significant, namely, 41.9% in G1 and 20.7% in G2 (P = .077). There were no differences between groups concerning mean, systolic and diastolic blood pressure, HbA1c, or creatinine at 12 months. This interim analysis showed no evidence of an increased risk of poorer performance among the early steroid reduction or safety differences in kidney transplant recipients versus a regular dosage steroid group of patients. Further analysis of the complete study data is underway.
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PMID:Corticosteroid reduction with tacrolimus (CORRETA) TRIAL: a prospective Brazilian multicenter, randomized trial of early corticosteroid reduction versus regular corticosteroid dosage maintenance on a tacrolimus (Prograf) and mycophenolate mofetil (Cellcept) immunosuppression regimen in kidney transplant recipients: interim analysis. 1845 88

Tacrolimus, a calcineurin inhibitor, has become an increasingly valuable tool in the treatment of dermatological disorders during the last few years. However, its effect on wound healing is still under investigation and remains the subject of safety concerns. A 75-year old woman with lichen planus, diabetes mellitus, and a foot ulcer was prescribed tacrolimus for the treatment of her lichen planus. After starting the treatment, her ulcer healed and the medication was discontinued. Shortly thereafter, re-ulceration occurred, treatment was re-introduced, and the wound continued to heal until treatment was discontinued. When the third course of tacrolimus was prescribed, the ulcer started healing again but a diagnosis of osteomyelitis necessitated surgical intervention. A review of the literature suggests that tacrolimus does not adversely affect healing in vivo or in vitro and may facilitate healing lower extremity skin ulcers, especially those of inflammatory origin. Studies are needed to clarify which lower extremity wounds would improve with tacrolimus.
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PMID:The effect of tacrolimus on lower extremity ulcers: a case study and review of the literature. 1848 May 4

Risk factors for new-onset diabetes after transplantation (NODAT) need to be assessed in large cohorts. We retrospectively evaluated the impact of early (3 and 6 months after transplantation) proteinuria, urinary albumin excretion (UAE) and arterial pressure on NODAT in 828 Caucasian renal transplant recipients (median follow-up: 5.3 years; 5832 patient-years). The 10- and 20-year incidence of NODAT was 15.0% and 22.0%, respectively. Low-grade (<1 g/day) (HR: 2.04 [1.25-3.33], p = 0.0042) and very low-grade (<0.3 g/day) (HR: 2.21 [1.32-3.70], p = 0.0025) proteinuria were independent risk factors for NODAT. There was a dose-dependent relationship across UAE categories (increasing risk from normoalbuminuria to macroalbuminuria) with NODAT. Tacrolimus, sirolimus and beta-blockers (HR: 1.86 [1.07-3.22], p = 0.0277) were significantly associated with NODAT even after multiple adjustments, but not diuretics, angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers. Systolic arterial pressure (HR per 10 mmHg: 1.16 [1.03-1.29], p = 0.0126) and pulse pressure (HR: 1.26 [1.12-1.43], p = 0.0002) were associated with NODAT. Only pulse pressure remained significant after adjustments. Patients at highest risks had early proteinuria and pulse pressure >60 mmHg. Early low-grade proteinuria and pulse pressure (in addition to beta-blockers) constitute independent risk factors for NODAT; they may be markers of the metabolic syndrome and/or vascular damage in renal transplant recipients.
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PMID:Early pulse pressure and low-grade proteinuria as independent long-term risk factors for new-onset diabetes mellitus after kidney transplantation. 1869 75

Renal transplant recipients have increased mortality rates when compared with the general population. The new immunosuppressive drugs have improved short-term patient survival up to 95% at 1-2 years, but these data have to be confirmed in long-term follow-up. Furthermore, no particular regimen has proved to be superior over others with regard to patient survival. Cardiovascular diseases are the most common cause of mortality in renal transplant recipients and while no immunosuppressive drug has been directly associated with cardiovascular events, immunosuppressive drugs have different impacts on traditional risk factors. Corticosteroids and ciclosporin are the agents with the most negative impact on weight gain, blood pressure and lipids. Tacrolimus increases the risk of new-onset diabetes mellitus. Sirolimus and everolimus have the most impact on risk factors for post-transplant hyperlipidaemia. Modifications in immunosuppression could improve the cardiovascular profile but there is little evidence regarding the beneficial effects of these changes on patient outcomes. Malignancies are also an increasing cause of mortality, overtaking cardiovascular disease in some series. Induction therapy, azathioprine and calcineurin inhibitors (CNIs) are probably the immunosuppressive agents most linked with post-transplant malignancies. Mycophenolate mofetil (MMF) has no negative impact on the incidence of malignancies. Target of rapamycin (mTOR) inhibitors have antioncogenic properties and they are associated with a lower incidence of malignancies. In addition, these agents have been recommended for use to decrease the dose or withdrawal of CNIs in patients with malignancies. Infections are still an important cause of morbidity and mortality in renal transplant recipients. Some immunosuppressive agents such as MMF increase the incidence of cytomegalovirus infection and the need for prophylactic measures in risk recipients. The use of potent immunosuppressive therapy has resulted in the appearance of BK virus nephropathy, which progresses to graft failure in a high percentage of patients. Although first associated with tacrolimus and MMF immunosuppression, recent data suggest that BK nephropathy appears with any kind of triple therapy. In conclusion, reducing risk factors for patient death should be a major target to improve outcomes after renal transplantation. Effort should be made to control cardiovascular diseases, malignancies and infections with improved use of immunosuppressive drugs. Preliminary results with belatacept suggest its safety and efficacy, and open new perspectives in the immunosuppression of de novo renal transplant recipients.
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PMID:Immunosuppressive drugs in kidney transplantation: impact on patient survival, and incidence of cardiovascular disease, malignancy and infection. 1985 26


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